抗α8整合素免疫脂质体在狼疮易感小鼠肾小球中的作用：一种将治疗剂递送至系统性红斑狼疮患者肾小球的新系统。
Anti-alpha8 integrin immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for delivery of therapeutic agents to the renal glomerulus in systemic lupus erythematosus.
作者信息
Scindia Yogesh, Deshmukh Umesh, Thimmalapura Pushpa-Rekha, Bagavant Harini
机构信息
University of Virginia, Charlottesville, VA 22908, USA.
出版信息
Arthritis Rheum. 2008 Dec;58(12):3884-91. doi: 10.1002/art.24026.
OBJECTIVE
Glomerular mesangial cells are active participants in the pathogenesis of lupus glomerulonephritis (GN). Thus, targeted delivery of therapeutic agents to mesangial cells would be an attractive approach to treatment. However, lack of known unique mesangial cell surface markers has hampered this process. This study was undertaken in a mouse model of lupus GN to identify mesangial markers and to develop a system for targeted drug delivery to the glomerulus.
METHODS
Based on previous observations, alpha8 integrin expressed on the surface of glomerular mesangial cells was selected as a target molecule for delivery. Two mouse strains susceptible to lupus GN, NZM2328 and (NZM2328 x NOD)F1, were studied. Glomerular expression of alpha8 integrin in normal and nephritic mice was confirmed by immunofluorescence and quantitative polymerase chain reaction analysis. Liposomes were formulated and conjugated with an anti-alpha8 integrin antibody. These immunoliposomes were loaded with DiI, a red fluorescent dye, to allow tracking in vivo, and injected into the tail vein of female mice at different ages. Specificity of targeting was studied by fluorescence microscopy and flow cytometry.
RESULTS
Expression of alpha8 integrin was observed in the glomeruli of normal and nephritic mice. Anti-alpha8 integrin immunoliposomes were detected in the glomerulus and glomerular mesangial cells after tail vein injection in normal and nephritic mice. Delivery of DiI by anti-alpha8 integrin immunoliposomes was tissue specific, being observed predominantly in the glomeruli, with some nonspecific uptake by CD11b cells.
CONCLUSION
These findings are the first demonstration of specific delivery of anti-alpha8 integrin immunoliposomes to the mesangium following tail vein injection in mice. Anti-alpha8 integrin immunoliposomes thus offer a novel approach for targeted drug therapy in lupus and other glomerular diseases.
目的
肾小球系膜细胞是狼疮性肾小球肾炎（GN）发病机制中的活跃参与者。因此，将治疗药物靶向递送至系膜细胞将是一种有吸引力的治疗方法。然而，缺乏已知的独特系膜细胞表面标志物阻碍了这一进程。本研究在狼疮性GN小鼠模型中进行，以鉴定系膜标志物并开发一种将药物靶向递送至肾小球的系统。
方法
基于先前的观察结果，选择在肾小球系膜细胞表面表达的α8整合素作为递送的靶分子。研究了两种易患狼疮性GN的小鼠品系，即NZM2328和（NZM2328×NOD）F1。通过免疫荧光和定量聚合酶链反应分析证实正常和肾炎小鼠中α8整合素的肾小球表达。制备脂质体并与抗α8整合素抗体偶联。这些免疫脂质体装载有红色荧光染料DiI，以便在体内进行追踪，并注射到不同年龄雌性小鼠的尾静脉中。通过荧光显微镜和流式细胞术研究靶向的特异性。
结果
在正常和肾炎小鼠的肾小球中观察到α8整合素的表达。在正常和肾炎小鼠尾静脉注射后，在肾小球和肾小球系膜细胞中检测到抗α8整合素免疫脂质体。抗α8整合素免疫脂质体递送DiI具有组织特异性，主要在肾小球中观察到，CD11b细胞有一些非特异性摄取。
结论
这些发现首次证明了在小鼠尾静脉注射后抗α8整合素免疫脂质体可特异性递送至系膜。因此，抗α8整合素免疫脂质体为狼疮和其他肾小球疾病的靶向药物治疗提供了一种新方法。
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